Mice Lacking the Circadian Modulators SHARP1 and SHARP2 Display Altered Sleep and Mixed State Endophenotypes of Psychiatric Disorders

Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/ BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2(-/-)) using online EEG recordings in living animals, behavioral assays and global gene expression profiling. EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2(-/-) mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and clock genes, particularly for SHARP1 and PER1. Our findings support the hypothesis that abnormal sleep and certain (endo) phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2

Hepatic p53 is regulated by transcription factor FOXO1 and acutely controls glycogen homeostasis

The tumor suppressor p53 is involved in the adaptation of hepatic metabolism to nutrient availability. Acute deletion of p53 in the mouse liver affects hepatic glucose and triglyceride metabolism. However, long-term adaptations upon the loss of hepatic p53 and its transcriptional regulators are unknown. Here we show that short-term, but not chronic, liver-specific deletion of p53 in mice reduces liver glycogen levels, and we implicate the transcription factor forkhead box O1 protein (FOXO1) in the regulation of p53 and its target genes. We demonstrate that acute p53 deletion prevents glycogen accumulation upon refeeding, whereas a chronic loss of p53 associates with a compensational activation of the glycogen synthesis pathway. Moreover, we identify fasting-activated FOXO1 as a repressor of p53 transcription in hepatocytes. We show that this repression is relieved by inactivation of FOXO1 by insulin, which likely mediates the upregulation of p53 expression upon refeeding. Strikingly, we find that high-fat diet-induced insulin resistance with persistent FOXO1 activation not only blunted the regulation of p53 but also the induction of p53 target genes like p21 during fasting, indicating overlapping effects of both FOXO1 and p53 on target gene expression in a context-dependent manner. Thus, we conclude that p53 acutely controls glycogen storage in the liver and is linked to insulin signaling via FOXO1, which has important implications for our understanding of the hepatic adaptation to nutrient availability

Empirical modelling of translation and interpreting

Empirical research is carried out in a cyclic way: approaching a research area bottom-up, data lead to interpretations and ideally to the abstraction of laws, on the basis of which a theory can be derived. Deductive research is based on a theory, on the basis of which hypotheses can be formulated and tested against the background of empirical data. Looking at the state-of-the-art in translation studies, either theories as well as models are designed or empirical data are collected and interpreted. However, the final step is still lacking: so far, empirical data has not lead to the formulation of theories or models, whereas existing theories and models have not yet been comprehensively tested with empirical methods. This publication addresses these issues from several perspectives: multi-method product- as well as process-based research may gain insights into translation as well as interpreting phenomena. These phenomena may include cognitive and organizational processes, procedures and strategies, competence and performance, translation properties and universals, etc. Empirical findings about the deeper structures of translation and interpreting will reduce the gap between translation and interpreting practice and model and theory building. Furthermore, the availability of more large-scale empirical testing triggers the development of models and theories concerning translation and interpreting phenomena and behavior based on quantifiable, replicable and transparent data

Empirical modelling of translation and interpreting

Empirical research is carried out in a cyclic way: approaching a research area bottom-up, data lead to interpretations and ideally to the abstraction of laws, on the basis of which a theory can be derived. Deductive research is based on a theory, on the basis of which hypotheses can be formulated and tested against the background of empirical data. Looking at the state-of-the-art in translation studies, either theories as well as models are designed or empirical data are collected and interpreted. However, the final step is still lacking: so far, empirical data has not lead to the formulation of theories or models, whereas existing theories and models have not yet been comprehensively tested with empirical methods. This publication addresses these issues from several perspectives: multi-method product- as well as process-based research may gain insights into translation as well as interpreting phenomena. These phenomena may include cognitive and organizational processes, procedures and strategies, competence and performance, translation properties and universals, etc. Empirical findings about the deeper structures of translation and interpreting will reduce the gap between translation and interpreting practice and model and theory building. Furthermore, the availability of more large-scale empirical testing triggers the development of models and theories concerning translation and interpreting phenomena and behavior based on quantifiable, replicable and transparent data

Empirical modelling of translation and interpreting

Empirical research is carried out in a cyclic way: approaching a research area bottom-up, data lead to interpretations and ideally to the abstraction of laws, on the basis of which a theory can be derived. Deductive research is based on a theory, on the basis of which hypotheses can be formulated and tested against the background of empirical data. Looking at the state-of-the-art in translation studies, either theories as well as models are designed or empirical data are collected and interpreted. However, the final step is still lacking: so far, empirical data has not lead to the formulation of theories or models, whereas existing theories and models have not yet been comprehensively tested with empirical methods. This publication addresses these issues from several perspectives: multi-method product- as well as process-based research may gain insights into translation as well as interpreting phenomena. These phenomena may include cognitive and organizational processes, procedures and strategies, competence and performance, translation properties and universals, etc. Empirical findings about the deeper structures of translation and interpreting will reduce the gap between translation and interpreting practice and model and theory building. Furthermore, the availability of more large-scale empirical testing triggers the development of models and theories concerning translation and interpreting phenomena and behavior based on quantifiable, replicable and transparent data

Empirical modelling of translation and interpreting

Empirical research is carried out in a cyclic way: approaching a research area bottom-up, data lead to interpretations and ideally to the abstraction of laws, on the basis of which a theory can be derived. Deductive research is based on a theory, on the basis of which hypotheses can be formulated and tested against the background of empirical data. Looking at the state-of-the-art in translation studies, either theories as well as models are designed or empirical data are collected and interpreted. However, the final step is still lacking: so far, empirical data has not lead to the formulation of theories or models, whereas existing theories and models have not yet been comprehensively tested with empirical methods. This publication addresses these issues from several perspectives: multi-method product- as well as process-based research may gain insights into translation as well as interpreting phenomena. These phenomena may include cognitive and organizational processes, procedures and strategies, competence and performance, translation properties and universals, etc. Empirical findings about the deeper structures of translation and interpreting will reduce the gap between translation and interpreting practice and model and theory building. Furthermore, the availability of more large-scale empirical testing triggers the development of models and theories concerning translation and interpreting phenomena and behavior based on quantifiable, replicable and transparent data

Empirical modelling of translation and interpreting

Empirical research is carried out in a cyclic way: approaching a research area bottom-up, data lead to interpretations and ideally to the abstraction of laws, on the basis of which a theory can be derived. Deductive research is based on a theory, on the basis of which hypotheses can be formulated and tested against the background of empirical data. Looking at the state-of-the-art in translation studies, either theories as well as models are designed or empirical data are collected and interpreted. However, the final step is still lacking: so far, empirical data has not lead to the formulation of theories or models, whereas existing theories and models have not yet been comprehensively tested with empirical methods. This publication addresses these issues from several perspectives: multi-method product- as well as process-based research may gain insights into translation as well as interpreting phenomena. These phenomena may include cognitive and organizational processes, procedures and strategies, competence and performance, translation properties and universals, etc. Empirical findings about the deeper structures of translation and interpreting will reduce the gap between translation and interpreting practice and model and theory building. Furthermore, the availability of more large-scale empirical testing triggers the development of models and theories concerning translation and interpreting phenomena and behavior based on quantifiable, replicable and transparent data

Empirical modelling of translation and interpreting

Empirical research is carried out in a cyclic way: approaching a research area bottom-up, data lead to interpretations and ideally to the abstraction of laws, on the basis of which a theory can be derived. Deductive research is based on a theory, on the basis of which hypotheses can be formulated and tested against the background of empirical data. Looking at the state-of-the-art in translation studies, either theories as well as models are designed or empirical data are collected and interpreted. However, the final step is still lacking: so far, empirical data has not lead to the formulation of theories or models, whereas existing theories and models have not yet been comprehensively tested with empirical methods. This publication addresses these issues from several perspectives: multi-method product- as well as process-based research may gain insights into translation as well as interpreting phenomena. These phenomena may include cognitive and organizational processes, procedures and strategies, competence and performance, translation properties and universals, etc. Empirical findings about the deeper structures of translation and interpreting will reduce the gap between translation and interpreting practice and model and theory building. Furthermore, the availability of more large-scale empirical testing triggers the development of models and theories concerning translation and interpreting phenomena and behavior based on quantifiable, replicable and transparent data

Empirical modelling of translation and interpreting

Empirical research is carried out in a cyclic way: approaching a research area bottom-up, data lead to interpretations and ideally to the abstraction of laws, on the basis of which a theory can be derived. Deductive research is based on a theory, on the basis of which hypotheses can be formulated and tested against the background of empirical data. Looking at the state-of-the-art in translation studies, either theories as well as models are designed or empirical data are collected and interpreted. However, the final step is still lacking: so far, empirical data has not lead to the formulation of theories or models, whereas existing theories and models have not yet been comprehensively tested with empirical methods. This publication addresses these issues from several perspectives: multi-method product- as well as process-based research may gain insights into translation as well as interpreting phenomena. These phenomena may include cognitive and organizational processes, procedures and strategies, competence and performance, translation properties and universals, etc. Empirical findings about the deeper structures of translation and interpreting will reduce the gap between translation and interpreting practice and model and theory building. Furthermore, the availability of more large-scale empirical testing triggers the development of models and theories concerning translation and interpreting phenomena and behavior based on quantifiable, replicable and transparent data

Empirical modelling of translation and interpreting

Empirical research is carried out in a cyclic way: approaching a research area bottom-up, data lead to interpretations and ideally to the abstraction of laws, on the basis of which a theory can be derived. Deductive research is based on a theory, on the basis of which hypotheses can be formulated and tested against the background of empirical data. Looking at the state-of-the-art in translation studies, either theories as well as models are designed or empirical data are collected and interpreted. However, the final step is still lacking: so far, empirical data has not lead to the formulation of theories or models, whereas existing theories and models have not yet been comprehensively tested with empirical methods. This publication addresses these issues from several perspectives: multi-method product- as well as process-based research may gain insights into translation as well as interpreting phenomena. These phenomena may include cognitive and organizational processes, procedures and strategies, competence and performance, translation properties and universals, etc. Empirical findings about the deeper structures of translation and interpreting will reduce the gap between translation and interpreting practice and model and theory building. Furthermore, the availability of more large-scale empirical testing triggers the development of models and theories concerning translation and interpreting phenomena and behavior based on quantifiable, replicable and transparent data